{"doi":"10.1016/j.celrep.2025.115831","title":"Deficiency in N-cadherin-Akt3 signaling impairs the blood-brain barrier","abstract":"The blood-brain barrier (BBB) restricts the passage of protein-rich fluids through tight junctions (TJs) formed between brain endothelial cells (BECs). BBB restrictiveness diminishes with aging, but the underlying mechanisms remain unclear. BECs establish physical contact with pericytes via N-cadherin homophilic adhesion. In cortex tissue from young and middle-aged patients, the age-related loss of vascular N-cadherin corresponds with the disruption of occludin TJs. Genetic deletion of N-cadherin in ECs impairs occludin TJs, leading to reduced cerebral tissue perfusion and spatial memory deficit. Mechanistically, the assembly of N-cadherin contacts stabilizes occludin TJs via the phosphoinositide 3-kinase p110β-Akt3 circuit, which is disrupted with aging. Furthermore, mutation of occludin Ser471 to Ala destabilizes occludin TJs even in the presence of N-cadherin contacts. These findings highlight a functional role for N-cadherin as a signaling hub that stabilizes occludin at TJs in a phosphorylation-dependent manner, thereby supporting BBB integrity.","journal":"Cell Reports","year":2025,"id":521384,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1022319,"name":"Wan Ching Chan","orcid":"0000-0002-0758-0066","position":1,"is_corresponding":false},{"id":911455,"name":"Shuangping Zhao","orcid":"0000-0003-1258-8852","position":2,"is_corresponding":false},{"id":1392240,"name":"Harry M Hailemeskel","orcid":null,"position":3,"is_corresponding":false},{"id":402182,"name":"Riya Thomas","orcid":"0000-0002-2559-1586","position":4,"is_corresponding":false},{"id":931919,"name":"Mohsin Zafar","orcid":"0009-0004-2960-7006","position":5,"is_corresponding":false},{"id":1126495,"name":"Fozia Mir","orcid":null,"position":6,"is_corresponding":false},{"id":235201,"name":"Péter T. Tóth","orcid":"0000-0003-2168-0124","position":7,"is_corresponding":false},{"id":271094,"name":"Kamran Avanaki","orcid":"0000-0002-1437-8456","position":8,"is_corresponding":false},{"id":402184,"name":"Leon M. Tai","orcid":"0000-0003-4430-6717","position":9,"is_corresponding":false},{"id":399163,"name":"Jeffrey A. Loeb","orcid":"0000-0003-2980-6377","position":10,"is_corresponding":false},{"id":533265,"name":"Yulia Komarova","orcid":"0000-0002-3526-6082","position":11,"is_corresponding":false},{"id":207338,"name":"Quinn Lee","orcid":null,"position":0,"is_corresponding":true}],"reference_count":134,"raw_metadata":null,"created_at":"2026-07-19T02:49:44.558743Z","pmid":"40503940","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}